The following plan will prepare Dr. Fox to investigate molecular mechanisms involved in immunoregulatory abnormalities of the gastrointestinal tract. Phase I of this plan will focus on acquiring fundamental knowledge and developing laboratory skills required for advanced work in molecular immunology and molecular genetics. This will occur under the guidance and direct supervision of Jon G. Seidman, Ph.D., Department of Genetics, Harvard Medical School. The proposed research project, "Structural and Functional Analysis of the Genomic V-J Interval in the T-cell Receptor Gamma Chain Locus," will serve as a vehicle for learning techniques essential to molecular genetics while dissecting a fundamental problem of immunology. The project will begin by using overlapping cosmids to generate a restriction enzyme map of the exact V-J distance. Identifying functional transcription products and tracking the ultimate fate of this piece of the genome will follow. Preliminary cell culture work with intestinal lymphocytes will prepare for the transition to Phase II. The Phase I research experience will be complimented by graduate level courses conducted at Harvard University, and by attending and participating in seminars at Harvard Medical School, Massachusetts Institute of Technology, Massachusetts General Hospital, and The Dana-Farber Cancer Institute. Phase II will ensue under the guidance of W. Allan Walker, M.D., Professor of Pediatrics, HMS, and Chief of the Combined Program of Pediatric Gastroenterology and Nutrition at The Children's Hospital and MGH. The knowledge and experience gathered from Phase I of this program will be applied to the study of gastrointestinal mucosal immunity and the molecular genetics of specific gastrointestinal disorders. This will begin by characterizing T- cell receptor rearrangements of cloned intestinal mucosal T cells from patients with gluten-sensitive enteropathy and expand to include analysis of genes encoding proteins unique to Kupffer cells.